The sensory and motor impairments associated with peripheral neuropathy lead to poor physical functioning, postural control and balance. These changes affect the activities of daily living and increase the risk of falling, subsequently leading to increased morbidity and decreased quality of life. [In an effort to maximize functional recovery from injuries, many veterans will undergo surgical procedures to their affected limbs.] Anesthesiologists commonly use local anesthetics (LAs) to perform peripheral nerve blocks that result in temporary control of pain during or after a surgical procedure. Peripheral nerve damage can occur as a complication from peripheral nerve blocks and the mechanism of injury remains unknown. It has been well documented that all LAs are toxic to neurons. Because LAs are frequently applied to sites in our veterans where peripheral nerves are diseased or injured, understanding their effects on injured neurons has important implications for clinical practice. Our long-term goal is [to maximize functional recovery in veterans suffering from nerve impairments] by understanding how LAs affect pre-existing peripheral nerve injuries. The objective is to determine if LAs worsen peripheral neuron cell death and/or slow functional recovery [in a chronic model] of peripheral nerve injury. Our central hypothesis is that previously injured neurons will be more susceptible to the toxicity of longer-acting LAs and this will result in increased neuron cell death and delayed or absent functional recovery in mice with a previous peripheral nerve injury compared to mice with no injury. The rationale for the proposed research is that an improved understanding of the effects of LAs on neurons will help identify veterans at higher risk for permanent neural deficits after peripheral nerve blocks and/or decrease the risk of neural deficit following peripheral nerve blocks. To test our central hypothesis we will pursue the following specific aims: Specific Aim 1: Determine if select LAs cause peripheral neuron cell death alone or exacerbate peripheral nerve cell death after a peripheral nerve axotomy or crush in a well-established mouse model of peripheral nerve injury. Select LAs or placebo (saline) will be applied to an intact facial nerve (sham injury), 1 week after a facial nerve axotomy, and 1 week after a facial nerve crush injury. Neuron survival will be determined 4-weeks after LA treatment by cell counts that compare between injured and uninjured nerves. Specific Aim 2: Determine if select LAs attenuate functional recovery after a peripheral nerve crush injury in a well-established mouse model of peripheral nerve injury. Select LAs or placebo (saline) will be applied to the facial nerve 1 week after a facial nerve crush injury. Neuronal regeneration will be measured by twice daily analysis of functional recovery from a nerve crush injury. [Specific Aim 3: Explore changes in gene expression of injured neurons treated with LAs identified from Aims 1 and 2. Mice will undergo a facial nerve axtotomy then select local anesthetic applied to the nerve 1 week after injury. We will then sacrifice animals at 0, 1, 3, 7, and 28 days following treatment and use laser capture microdissection to collect tissue from the injured and uninjured facial nuclei to analyze genes associated with regeneration, apoptosis, stress response and sodium channel components.] The expected outcomes of the proposed research are to identify commonly used LAs that worsen neuron cell death and/or slow functional recovery after a peripheral nerve injury, and to further characterize changes in gene expression. Such results are expected to have an important positive impact, by identifying patients at higher risk for permanent neural deficits or help identify LAs with safer neurotoxicity profiles. The knowledge gained from these studies may impact how clinicians choose appropriate patients to receive peripheral nerve blocks and/or influence which LAs are used on at-risk patients.